The following description of the background of the invention is provided as an aid to understanding the invention and is not admitted to describe or constitute prior art to the invention.
This application concerns novel methods which enable golimumab, an anti-TNF biologic and other molecules, to cross the blood-brain barrier, the blood-eye barrier, and/or the blood-nerve barrier and therefore be of therapeutic use in humans and other mammals. Included among these methods are those which involve perispinal administration of golimumab without direct intrathecal injection. In addition, additional methods involve the perispinal administration of other molecules, as detailed herein. Perispinal administration is defined as administration of the molecule into the anatomic area within 10 cm of the spine. Perispinal administration results in absorption of golimumab or other molecules given by perispinal administration, into the vertebral venous system. The vertebral venous system is capable of transporting therapeutic molecules to the head, including into the brain, the eye, the retina, the auditory apparatus, the cranial nerves or the head, via retrograde venous flow, thereby bypassing the blood-brain barrier and delivering the molecules to the brain, the eye, the retina, the auditory apparatus, the cranial nerves or the head.
This method may be utilized for a wide variety of large molecules, including, but not limited to, recombinant DNA therapeutics, other biologics, monoclonal antibodies, fusion proteins, monoclonal antibody fragments, hormones, cytokines, anti-cytokines, interleukins, anti-interleukins, interferons, colony-stimulating factors, cancer chemotherapeutic agents, growth factors, anti-virals and antibiotics.
In addition the methods of the present invention may be used to deliver molecules with a MW less than 2,000 daltons to the brain and other structures of the head more efficiently than if delivered systemically, and these methods utilizing these smaller molecules are also to be considered a part of this invention.
In addition to human use, these methods may be used to treat other mammals, including horses, dogs, and cats.
This method may be used for delivery for humans or other mammals with neurodegenerative diseases, including Alzheimer's Disease, Parkinson's Disease, amyotrophic lateral sclerosis; for eye disorders or diseases including, but not limited to, macular degeneration, diabetic retinopathy, sympathetic opthalmia and retinitis pigmentosa; disorders of hearing, including, but not limited to sensorineural hearing loss or presbycusis; central nervous system (CNS) tumors, including tumors of the brain; for other diseases or disorders of the brain, including, but not limited to vascular disorders such as stroke, transient ischemic attack, vascular dementia, and cerebrovascular disease; infectious diseases of the CNS, including viral and bacterial infections; for sciatica, cervical radiculopathy, and other forms of disc-related pain; for low back pain; other diseases or disorders involving the spine, the spinal cord, the spinal nerve roots, the brain, eyes, auditory apparatus, or other structures of the head.
The use of cytokine antagonists to treat neurological disorders is the subject of several previous patents of this inventor, including U.S. Pat. Nos. 6,015,557, 6,177,077, 6,419,934 6,419,944, 6,423,321, 6,428,787, 6,537,549, 6,623,736 and US patent applications 20030049256 and U.S. patent application Ser. No. 11/016,047, filed Dec. 18, 2004, entitled “Methods of use of etanercept to improve human cognitive function”, and provisional U.S. patent application 60/585,735, filed Jul. 6, 2004. These issued patents, patent applications, and provisional patent applications are incorporated in their entirety herein. This invention includes further applications of these ideas.
The adverse biologic effects of excess TNF can be reduced by the use of biologic inhibitors of TNF. These inhibitors can be divided into two broad categories: monoclonal antibodies and their derivatives; and TNF binding biologics which are not antibody based. In the first category belong golimumab, also known as CNTO-148 (Centocor, Schering-Plough), infliximab (Remicade®, Centocor), adalimumab (Humira®, Abbott), and CDP 870 (Celltech). The second category includes etanercept, soluble TNF receptor type 1, pegylated soluble TNF receptor type 1 (Amgen) and onercept (Serono). Etanercept has a serum half life of approximately 4.8 days when administered to patients with rheumatoid arthritis on a chronic basis; onercept has a serum half-life which is considerably shorter, and it is usually administered at least three times weekly when used to treat systemic illnesses.
Golimumab has many biologic effects. Golimumab, for example, in addition to being a potent anti-inflammatory also has important anti-apoptotic effects which may be of particular importance in treating neurological disorders, such as certain forms of dementia, where apoptosis plays a pathogenetic role.
Antibodies (immunoglobulins) are proteins produced by one class of lymphocytes (B cells) in response to specific exogenous foreign molecules (antigens). Monoclonal antibodies (mAB), identical immunoglobulin copies which recognize a single antigen, are derived from clones (identical copies) of a single B cell. This technology enables large quantities of an immunoglobulin with a specific target to be mass produced.
Monoclonal antibodies with a high affinity for a specific cytokine will tend to reduce the biologic activity of that cytokine. Substances which reduce the biologic effect of a cytokine can be described in any of the following ways: as a cytokine blocker; as a cytokine inhibitor; or as a cytokine antagonist. In this patent, the terms blocker, inhibitor, and antagonist are used interchangeably with respect to cytokines.
Advances in biotechnology have resulted in improved molecules as compared to simply using monoclonal antibodies. One such molecule is CDP 870 which, rather than being a monoclonal antibody, is a new type of molecule, that being an antibody fragment. By removing part of the antibody structure, the function of this molecule is changed so that it acts differently in the human body. Another new type of molecule, distinct from monoclonal antibodies and soluble receptors, is a fusion protein. One such example is etanercept. This molecule has a distinct function which acts differently in the human body than a simple soluble receptor or receptors.
Monoclonal antibodies, fusion proteins, and all of the specific molecules discussed above under the categories of TNF antagonists and interleukin antagonists are considered biologics, in contrast to drugs that are chemically synthesized. For the purpose of this patent a biologic is defined as a molecule produced through recombinant DNA technology which is derived from the DNA of a living source. The living sources may include humans, other animals, or microorganisms. The biologics mentioned above are manufactured using biotechnology, which usually involves the use of recombinant DNA technology. Cytokine antagonists are one type of biologic. Biologics are regulated through a specific division of the FDA.
Cytokine antagonists can take several forms. They may be monoclonal antibodies (defined above). They may be a monoclonal antibody fragment. They may take the form of a soluble receptor to that cytokine. Soluble receptors freely circulate in the body. When they encounter their target cytokine they bind to it, effectively inactivating the cytokine, since the cytokine is then no longer able to bind with its biologic target in the body. An even more potent antagonist consists of two soluble receptors fused together to a specific portion of an immunoglobulin molecule (Fc fragment). This produces a dimer composed of two soluble receptors which have a high affinity for the target, and a prolonged half-life. This new molecule is called a fusion protein. An example of this new type of molecule, called a fusion protein, is etanercept (Enbrel®).
TNF, a naturally occurring cytokine present in humans and other mammals, plays a key role in the inflammatory response, in the immune response and in the response to infection. TNF is formed by the cleavage of a precursor transmembrane protein, forming soluble molecules which aggregate in vivo to form trimolecular complexes. These complexes then bind to receptors found on a variety of cells. Binding produces an array of pro-inflammatory effects, including release of other pro-inflammatory cytokines, including IL-6, IL-8, and IL-1; release of matrix metalloproteinases; and up regulation of the expression of endothelial adhesion molecules, further amplifying the inflammatory and immune cascade by attracting leukocytes into extravascular tissues.
Golimumab is currently in clinical development by Centocor/Schering-Plough for treatment of rheumatoid arthritis, with potential applications for uveitis, asthma, and Crohn's Disease. It may be described as a immunoglobulin G1, anti-(human tumor necrosis factor α) (human monoclonal CNTO 148 γ1-chain), disulfide with human monoclonal CNTO 148 κ-chain), dimer, and has CAS Registry number 476181-74-5. It is a fully human anti-TNF monoclonal antibody.
Etanercept (Enbrel®, Amgen/Immunex), golimumab, infliximab (Remicade®, Centocor), adalimumab (Humira®, Abbott), CDP 870, and onercept are potent and selective inhibitors of TNF. CDP 870, golimumab and onercept are in clinical development. Etanercept, adalimumab, and infliximab are FDA approved for chronic systemic use to treat rheumatoid arthritis and certain other chronic inflammatory disorders. Golimumab has a molecular weight of approximately 147,000 daltons.
Bevacizumab (Avastin™, Genentech) is a recombinant humanized monoclonal IgG1 antibody that binds to and inhibits the biologic activity of human vascular endothelial growth factor (VEGF) and which may be useful for the treatment of various malignancies. Bevacizumab has a molecular weight of 149,000 daltons and is therefore too large to readily cross the blood-brain barrier if administered systemically.
Etanercept can also be designated as TNFR:Fc because it is a dimeric fusion protein consisting of two soluble TNF receptors fused to a Fc portion of an immunoglobulin molecule. This fusion protein functions in a manner quite distinct from a simple soluble TNF receptor. Soluble TNF receptors are normally present in the human body. But the use of these soluble TNF receptors as therapeutic agents for the treatment of the conditions of consideration in this patent is made impractical by their extremely short half-life and therefore their limited biologic activity. The present invention utilizing etanercept is therefore distinguished from an invention specifying the use of a soluble TNF receptor. It is incorrect and imprecise to describe etanercept as a soluble TNF receptor because this is an incorrect description of its complex structure and omits characteristics of etanercept which are absolutely essential to its function. This is further underscored by the developmental history of etanercept. In its first iteration the precursor molecule to etanercept was produced with a single TNF receptor fused to an immunoglobulin fragment. The biologic activity of this molecule was poor. Therefore not only is etanercept distinguished from a soluble TNF receptor, it is also distinguished from a TNF-binding fusion protein which contains the recombinant DNA sequence of only a single soluble TNF receptor. The unique structure of etanercept, containing a dimer (two) soluble TNF receptors fused to an Fc portion of an immunoglobulin molecule, is necessary for the proper performance of the present invention. Since etanercept has the molecular structure of a fusion protein it is thus quite distinct from both onercept, soluble TNF receptor type 1 and pegylated soluble TNF receptor type 1.
The vertebral venous system can also be used to deliver other types of therapeutic agents to the cerebral cortex, eye, retina, cerebellum, brainstem, eighth cranial nerve, cochlea, inner ear, and cerebrospinal fluid. These therapeutic agents include pharmacologic agents, other cytokine antagonists, and growth factors which affect neuronal function, or the immune response impacting neuronal function, including, but not limited to: interleukins including IL-1, IL-2, IL-4, IL-6, IL-10, and IL-13; interleukin 1 antagonists, such as IL-1 RA (Kineret®, Amgen) and IL-1 Trap; fusion proteins, such as IL-10 fusion protein and etanercept (Enbrel®, Immunex); human growth hormone and related biologics (recombinant human growth hormone, Humatrope® (somatropin) Eli Lilly & Co., Nutropin®/Nutropin AQ® (somatropin), Geref® (sermorelin) Serono, and Protropin® (somatrem) Genentech)); BDNF; erythropoietin (Epogen® (epoetin alpha) Amgen, Procrit® (epoetin alpha) Johnson & Johnson); G-CSF (Neupogen® (filgrastim), Amgen); GM-CSF; Intron® A (interferon alfa-2b) Schering-Plough; Avonex® (interferon beta-1a) Biogen; bevacizumab (Avastin™, Genentech); pegaptanib, ranibizumab, and other biologic VEGF antagonists; alefacept (LFA-3/lgG1 human fusion protein, Amevive® Biogen); Epidermal growth factor; anti-EGF (ABX-EGF, Abgenix); transforming growth factor-beta 1 (TGF-beta 1); NGF, or other compounds with CNS, vascular or immune therapeutic activity. Perispinal delivery is particularly advantageous when biologics, such as etanercept, which profoundly affect neuronal function, are administered because of their efficacy at extremely low concentration (high biologic potency).
This method may be used for delivery for humans or other mammals with neurodegenerative diseases, including Alzheimer's Disease, Parkinson's Disease, amyotrophic lateral sclerosis; for eye disorders or diseases including, but not limited to, macular degeneration, diabetic retinopathy, sympathetic opthalmia and retinitis pigmentosa; disorders of hearing, including, but not limited to sensorineural hearing loss or presbycusis; central nervous system (CNS) tumors, including tumors of the brain; for other diseases or disorders of the brain, including, but not limited to vascular disorders such as stroke, transient ischemic attack, vascular dementia, and cerebrovascular disease; infectious diseases of the CNS, including viral and bacterial infections; for sciatica, cervical radiculopathy, and other forms of disc-related pain; for low back pain; other diseases or disorders involving the spine, the spinal cord, the spinal nerve roots, the brain, eyes, auditory apparatus, or other structures of the head.
Localized administration for the treatment of localized clinical disorders has many clinical advantages over the use of conventional systemic treatment. Locally administered medication after delivery diffuses through local capillary, venous, arterial, and lymphatic action to reach the therapeutic target. In addition local administration of a large molecule, such as goliumumab, defined as a molecule with a molecular weight greater than or equal to 2,000 daltons, in the vicinity of the spine (perispinal administration) without direct intrathecal injection has the key advantage of improved delivery of the molecule to the brain and across the blood-brain barrier (BBB), with delivery enhanced by transport via the vertebral venous system. Intrathecal injection delivers the molecule into the cerebrospinal fluid (CSF), but has disadvantages of possible infection, hemorrhage, and subsequent CSF leak.
The BBB is a physiologic barrier which separates the brain and cerebrospinal fluid from the blood. It consists of a layer of cells which comprise the cerebral capillary endothelium, the choroid plexus epithelium, and the arachnoid membranes, which are connected by tight junctions (zonulae occludens). These tight junctions may be as much as 100 times tighter than junctions of other capillary endothelium, and prevent molecules larger than about 600 daltons in molecular weight (MW) from traversing the BBB when the molecule is administered systemically i.e. by conventional subcutaneous, intramuscular, or intravenous injection at an anatomic site remote from the spine.
The vertebral venous system (VVS) is an interconnected plexus of veins which surrounds the spinal cord and extends the entire length of the spine. This venous system provides a vascular route from the pelvis to the cranium which richly involves the bone marrow of the spine and which is functionally distinct from the systemic venous system. First described by Willis in 1663, the functional significance of the vertebral venous system was largely unappreciated until the work of Batson, who in 1940 proposed that this venous plexus provided the route by which prostate cancer metastasizes to the vertebral column. Acceptance of Batson's proposal by the medical community has led to the designation of the vertebral venous system as Batson's Plexus. Although now widely appreciated as a possible route by which cancer cells may spread to the spine there have been no previous suggestions that Batson's plexus may be of therapeutic usefulness. The use of Batson's plexus as route of delivery of biologics for clinical use, and as a route for delivery of large molecules to the brain, the eye, the retina, the auditory apparatus, the cranial nerves or the head are inventions of the author. This patent is a continuation to the methods of use of Batson's plexus to deliver therapeutic molecules to the nervous system which has been previously proposed by the inventor, and incorporates the previous patents and patent applications discussing this. In addition this patent is related to provisional U.S. patent application 60/662,744 entitled “Methods of Use of the Vertebral Venous System to Deliver Biologics to the CNS” filed Mar. 16, 2005, and application Ser. No. 10/269,745, entitled “Cytokine antagonists for neurological and neuropsychiatric disorders”, filed Oct. 9, 2002, and each of these patent applications are hereby incorporated herein in their entirety.
Perispinal administration involves anatomically localized delivery performed so as to place the therapeutic molecule directly in the vicinity of the spine at the time of initial administration. For the purposes of this patent, “in the vicinity of” is defined as within 10 centimeters. Perispinal administration includes, but is not limited to, the following types of administration: parenteral; subcutaneous; intramuscular; or interspinous; and specifically includes the use of interspinous injection carried through the skin in the midline of the neck or back, directly overlying the spine.
For the purposes of this patent perispinal administration excludes intrathecal administration, which carries additional risks of infection and hemorrhage. Therefore in this patent “perispinal” is more exactly defined as “perispinal (extrathecal)”, but for the purposes of brevity shall be designated throughout simply as “perispinal”. Perispinal administration leads to enhanced delivery of large molecules to the brain and the head and the structures therein in a therapeutically effective amount. The conventional mode of delivery of these molecules for clinical applications, i.e. subcutaneous administration in the abdomen, thighs, or arms, does not effectuate delivery across the blood-brain barrier (see Robinson reference 60) which is as efficient as perispinal administration and is therefore distinguished from the perispinal methods of administration described in this invention.
Hearing loss occurs in humans in many forms. Hearing is essential to the normal conduct of one's daily activities and people with impaired hearing have many difficulties. Hearing loss can date from birth; it can be acquired later in life; or it can be the result of trauma, accident, disease, or a toxic effect of a medication. It can be genetic, either as a solitary disorder or as part of a complex syndrome. Hearing loss is one of the most common chronic neurological impairments, estimated to affect about 4 percent of those under 45 in the United States, and about 29 percent of those 65 years or older.
As defined herein, the auditory apparatus includes the cochlea, the auditory division of the eighth cranial nerve, and the central auditory pathways. Sensorineural hearing loss is one particular category of hearing loss and is caused by lesions of the cochlea and/or the auditory division of the eighth cranial nerve. Prior to this invention, treatment of this condition was primarily limited to the use of hearing aids.
The pathogenetic mechanism of most forms of hearing loss has yet to be fully defined. Hearing loss can be due to conductive problems, which is not the subject of this patent; central hearing loss due to lesions of the central auditory pathway; or sensorineural hearing loss.
Humans react to sounds that are transduced into neurally conducted impulses through the action of neuroepithelial cells (hair cells) and spiral ganglion cells (neurons) in the inner ear. These impulses are transmitted along the cochlear division of the eighth cranial nerve into the brainstem and the central auditory pathways.
Presbycusis, or age-related hearing loss, is a type of sensorineural deafness which affects one-third of the population over the age of 75. The exact mechanism of presbycusis is unknown, and has long been thought to be multifactorial. Inflammation has not previously been thought to be a significant factor in the pathogenesis of presbycusis. Yet a previous study did suggest that genes encoded by the major histocompatibility complex (MHC) had a role in certain hearing disorders. (Bernstein, Acta Otolaryngol 1996 September; 116(5):666-71). The MHC is known to be central to the immune response and inflammation.
As will be discussed below there is now clinical evidence that inflammation has a role in the pathogenesis of various types of sensorineural hearing loss, including presbycusis. This opens up a new avenue of treatment of these disorders utilizing large molecules delivered by perispinal administration without direct intrathecal injection, including biologic TNF inhibitors and other large molecules with a molecular weight equal to or greater than 2,000 daltons.
As discussed in the previous patents and patent applications of the inventor, including U.S. Pat. Nos. 6,082,089; 6,537,549, and the others as enumerated above, including those detailed in section 1 of this application, the methods of the present invention may be utilized to treat sciatica, cervical radiculopathy, fibromyalgia, severe low back pain and/or related pain conditions, including neuropathic pain.